Inhibition of cystathionine-gamma-lyase and the biosynthesis of endogenous hydrogen sulphide ameliorates gentamicin-induced nephrotoxicity

Kinobe, Robert T., Van , Dam P., Scott, Jennifer L., Hall, Christine, Blyth, Scott, Reilly, Laurie, and Ross, Anthony (2011) Inhibition of cystathionine-gamma-lyase and the biosynthesis of endogenous hydrogen sulphide ameliorates gentamicin-induced nephrotoxicity. In: Proceedings of the The Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists, 1- 1. From: Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists, 4-9 December 2011, Perth, WA, Australia.

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Abstract

Introduction: Gentamicin is a commonly used antibiotic against infectious Gram negative bacteria. However, the clinical use of gentamicin over prolonged periods is limited because of dose- and time-dependent nephrotoxicity. Primarily, lysosomal phospholipidosis, generation of intracellular reactive oxygen species and heightened inflammation have been implicated. Hydrogen sulphide (H2S) is a small gaseous, endogenously produced signal transduction molecule with antioxidant, anti-inflammatory, antiapoptotic and cytoprotective properties. In kidneys for example, the production of endogenous H2S by cystathionine-γ-lyase was found to limit oxidative stress, renal ischemic-reperfusion injury and dysfunction. We hypothesized that H2S ameliorates gentamicin-induced toxicity, preventing nephron necrosis and renal dysfunction.

Methods: Adult female Sprague-Dawley rats were divided into six groups (n = 4–8 animals) and then treated for 10 days with; physiological saline only, sodium hydrosulphide (NaHS; an exogenous H2S-donor, 50 μmoles/Kg/day, i.p) only, DL-propargyl glycine (PAG; an irreversible inhibitor of cystathionine-γ-lyase, 25 mg/Kg/day, i.p) only, gentamicin (100 mg/Kg/day, i.p) only, a combination of getamicin and NaHS, or gentamicin and PAG respectively. Blood samples and kidneys were collected for biochemical, histological and morphometric analysis.

Results & Discussion: Nephrotoxic effects of gentamicin were not altered by administering NaHS but PAG significantly attenuated the toxic effects of gentamicin thus improving renal function (* P < 0.001 compared to saline controls and # P < 0.001 compared to gentamicin only). Gentamicin-induced histopathological changes including tubular necrosis, oedema and infiltration of the interstitium by inflammatory cells were attenuated by co-administering gentamicin with PAG. These data show that inhibition of the endogenous biosynthesis of H2S reduces gentamicin-induced renal damage. This effect might be related, at least in part, to the reduced inflammatory responses observed in animals treated with both gentamicin and PAG. Endogenous H2S and enzyme systems involved in its biosynthesis may offer a viable therapeutic target in alleviating the nephrotoxic effects of gentamicin.

Item ID: 22847
Item Type: Conference Item (Poster)
Date Deposited: 20 Aug 2012 05:41
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1115 Pharmacology and Pharmaceutical Sciences > 111501 Basic Pharmacology @ 50%
11 MEDICAL AND HEALTH SCIENCES > 1115 Pharmacology and Pharmaceutical Sciences > 111506 Toxicology (incl Clinical Toxicology) @ 50%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920103 Cardiovascular System and Diseases @ 100%
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